It is well known the wide interest on platinum(II) and Platinum(IV) complexes as anti-tumour agents.
The anti-tumour activity of four platinum compounds in animal models was first reported in 1969 (B. Rosemberg et al., Nature 222, 385, 1969). This followed the observation that filamentous growth occurred when cultures of E. Coli were subjected to an electric field and the realization that certain cis-diamino-platinum complexes were the cause of this effect (B. Rosenberg et al., Nature, 205, 965, 1965).
The anti-tumour activity of said platinum(II) complexes has been demonstrated in several animal models. These compounds inhibit tumors such as ascitic leukaemia, Walker-256 carcinosarcoma, mammary tumors induced by dimethylbenzanthracene and B-16 ascitic melanoma. It is estimated that over 2,000 analogues of the original platinum compounds have been synthetized and tested throughout the world since that time.
For a review see P.C. Hydes and M.J.H. Russell, Cancer and metastasis reviews, 7, 67, 1988. Among these compounds, cis-diammino-dichloro-platinum (cDDP, cisplatin) has been the most studied one, and nowadays it has entered clinical practice after approval for the treatment of testicular and ovarian cancer in 1978.
Also other platinum(II) complexes have been studied successfully on animal models (see for example "Platinum, Gold and other metal chemotherapeutic agents", S. J. Lippard Ed., ACS Symp. Series, 209, Washington D.C., 1983).
The antitumour activity of cisplatin has been well-documented in patients affected with various tumours, being particularly effective in the treatment of genito-urinary tumours, of neck and head tumours. Further clinical observations confirm efficacy of cisplatin in several human tumors, when administered in combination with other chemotherapeutic agents.
Due to important gastrointestinal and renal side-effects, haematologic and neurologic complications (ototoxicity) following cisplatin use, there is a increasing demand for novel platinum compounds provided with a better therapeutical index, and devoid of cross resistance with cisplatin.
Subsequent selection and evaluation processes resulted in the approval of carboplatin for use in the treatment of ovarian and small cell lung cancer in 1986. Carboplatin is reported to be less nephrotoxic than cis-platin.
Cisplatin and carboplatin (albeit at higher dose levels) show a similar spectrum of activity as other platinum compounds under clinical investigation.
At present time, the major requirement for a new drug is that it exerts a wider spectrum of clinical activity. In spite of all these efforts the results are not always encouraging both due to considerable toxicity and unfavourable lypophilic and hydrophilic properties of many of new platinum(II) complexes (see for example J. Clin. Hematol. Oncol. 12, 29, 1982). Poor solubility and stability in aqueous vehicles used for administration to patients represent one of the most serious obstacles for the clinical use of new compounds.
To overcome these difficulties, platinum(II) complexes endowed with additional basic or acid groups in neutral ligands and/or in leaving groups have been synthetized and screened The additional (basic and acid) functional groups were thought to be particularly suitable for achieving solubilization after salificaticn of the complexes with an appropriate counter-ion at the moment of dissolution in aqueous media.
Examples of said compounds are for ex.: cis-diamino-2-amino-malonate-platinum(II) complexes (Gandolfi O., U.S. Pat. No. 4,614,811, 1986); bis-platinum(II) complexes disclosed in U.S. Pat. No. 4,565,884 wherein the central polyfunctionalized leaving group is provided with an additional acid group; aromatic dicarboxylato derivatives of diamino-cyclopentane platinum(II) containing SO.sub.3 H and CO.sub.2 H groups in the aromatic ring (D.C. Craciunescu et al., J. Pharm. Belg., 41, 286, 1986); water-soluble bis(ascorbato) platinum(II) complexes A. R. Amudsen and E. W. Stern, U.S. Pat. Nos. 4,457,926; 4,462,998; 4,505,928; M. P. Hacher et al., Cancer Res., 45, 4748, 1985). All these substances have been claimed to be effective anti-tumour agents.
Many of them, when tested in different animal models, were found to show higher activities than cisplatin in P368, L1210 and ADJ/PC6 murine tumour models, albeit sometimes at higher dose levels.
It should be noted that the drugs were administered i.p., the site of tumour implant, for both the P388 and L1210 tumour lines. It is also possible that a local, rather than systemic, antitumour effect was observed in many of these cases.
There is a very marked trend to believe that the presence of ionic charges in platinum(II) complexes would be strongly detrimental and limiting the permeability across cell membranes, thus hindering the diffusion inside the cells and consequently the systemic effectiveness.
The synthesis of platinum complexes with functionalised amine ligands was largerly part of an attempt to vary the solubility characteristics of the complex and, indirectly, its tissue distribution. This was achieved in part by using a range of single functional groups e.g. hydroxyl and carboxylate substituents) that are expected to change the solubility of the parent compound. Amino and polyamino-sugars have been used as neutral ligands, too.
In order to improve activity, particularly on tumours that are refractory to platinum, toxicity or high dose levels are a necessary compromise unless a degree of selectivity can be conferred on the molecule.
One approach recently considered is to target the molecules to hormone receptor sites in a hormone dependent mammary carcinoma (see for ex. B. Wappes et al., J. Med. Chem., 27,1280, 1984).
An alternative approach for targeting platinum compounds uses immunoglobulins (Ig) with specific binding activity for particular cell types; or complexes attached to monoclonal antibodies against three Lewis Lung tumour lines (R. Arnon et al., Eur Pat. 0099133A 1984). Preliminary "in vivo" data suggest greater potency and lower toxicity than cisplatin and its analogues, although supportive data were not presented More recently, EP 0169645 has disclosed platinum(II) ccmplexes with very high selectivity of action when a malonate platinum(II) complex is linked to a monoclonal antibody, preferably through a polymethylene chain that is connecting the leaving malonic residue of the platinum complex with the targeting antibody.
In the above-mentioned targeting monoclonal antibody platinum complexes, the connecting polymethylene may be also interrupted by oxygen atoms to form a polyoxyethylene chain. To this purpose, it is generically described the synthesis of intermediate malonate platinum(II) complexes wherein the C.sub.2 carbon atom of the malonic leaving ligand is substituted by a --(CH.sub.2 CH.sub.2 --O).sub.3 H chain, and the final hydroxy group is suitably utilized for the desired conjugation with the monoclonal antibody. It is also generically disclosed that the single intermediate malonate platinum(II) complexes provided with polymethylene and/or polyoxyethylene chains, not bound with monoclonal antibody, may be effective as anti-tumour agents, although supportive data were not referred.
If one recalls that the preclinical evaluation of anti-tumour agents has relied upon animal tumours models, which are often poorly predictive of human cancer, then the difficulty of developing a drug with a new spectrum of activity becomes clear.
The design of cisplatin analogues for clinical application requires a judicious balance of the reactivity of the complex with its solubility in aqueous and lipid phases. While good water solubility is desiderable, it is generally achieved by using reactive leaving groups such as sulphate or nitrate, resulting in consequent toxicity, or chelating carboxylates that stabilise the molecule with a corresponding decrease in potency. In opposition, many compounds that show good anti-tumour activity in animal models are lipophilic and are administered as solutions or suspensions in peanut oil or as suspensions in aqueous media. The aqueous solubility of these compounds is too low to allow clinical evaluation of their properties via i.v. delivery.
The present invention relates to novel platinum(II) complexes which are endowed with intrinsically high solubility in aqueous media together with high lipophilic properties. The outstanding characteristics of the platinum(II) complexes of the present invention are achieved by the design of novel leaving ligands carrying polyoxyethylene substructures of increasing molecular weights. These substructures may be formed by linear polyoxyethylene chains and/or by cyclic polyoxyethylene residues, differently linked to malonic and to 1,4-butanedioic acids to better modulate the lipophilicity of the overall complex.
In accordance with the scope of the present invention the presence in the leaving group of linear and/or cyclic polyoxyethylene subunits of appropriate molecular weights enables to reach high solubilities in the aqueous media, and above all gives to the new molecules suitable lipophilic characteristics for improving their targeting to, penetration into and diffusion across the cell membranes.
In fact platinum(II) complexes of the present invention are provided both with hydrosolubility and with lipophilic properties. High hydrosolubility enables preparation of pharmaceutical compositions with high concentrations of the active principle; the administration of the drug to the patients may usefully result more comfortable, too. The more equilibrated balance of lipophilicity with hydrosolubility should favour high distribution of novel drugs in biological fluids, a proper interaction with cell membranes, an increased and selective tropism towards tumor cells, a wider spectrum of action, long-lasting biological effects and consequently more favourable therapeutical index.